Aza-dibenzocycloheptenes are described in U.S. Pat. No. 3,326,924 as having antihistaminic, antiserotonin and antianaphylactic activity and as useful in the treatment of allergic disorders such as urticaria, seasonal rhinitis and pollen sensitivity. One of these compounds is azatadine which is represented by the following formula: ##STR1## This compound is an antihistamine used in treatment of colds.
According to U.S. Pat. No. 3,326,924, the benzenoid portion of the aza-dibenzocycloheptene nucleus may be substituted by substituents such as lower alkyl, halogen, trifluoromethyl, hydroxy and lower alkoxy. The intermediates and process of the present invention are useful in preparing azatadine as well as the substituted compounds.
In a process described in U.S. Pat. No. 3,326,924, 3-(2-phenethyl)-2-cyanopyridine is prepared by reacting 3-(2-phenethyl)pyridine-1-oxide with dimethylsulfate and then with aqueous sodium cyanide. A process to convert the cyanopyridine to an aza-dibenzocycloheptene by cyclizing to give the 5-keto-aza-dibenzocycloheptene, then reacting with a Grignard reagent, e.g., 1-methyl-4-piperidinyl magnesium chloride, to give a 5-(1-methyl-4-piperidinyl)aza-dibenzocycloheptene-5-ol, which is dehydrated to give the exocyclic 5-(1-methyl-piperidylidenyl) compound, e.g., azatadine, is also described in U.S. Pat. No. 3,326,924.
It has been reported by Fife et al., Heterocycles 22:1121-4(1984) that 3-methyl-1-methoxypyridinium methylsulfate reacted with cyanide ion to give 3-methyl-2-cyanopyridine and "high percentages" of the 4-cyanopyridine isomer. In Table 1 on page 1122, Fife et al. reported that the 4-cyano compound was gobtained in 69% yield and 3-methyl-2-cyanopyridine was obtained in 24% yield.
Also, Fife et al., cited hereabove and Heterocycles 22:93-96(1984), reported the reaction of 3-methylpyridine-1-oxide with dimethyl-carbamoyl chloride to give 3-methyl-1-dimethylcarbamoyloxypyridinium chloride. Reaction of this pyridinium salt with potassium cyanide in water gave 3-methyl-2-cyanopyridine (89%) and the 6-isomer (11%).
A review entitled "Cyanation in the Pyridine Series: Synthetic Applications of the Reissert-Henze and Related Reactions" by Fife et al., Heterocycles 22:2375-2394(1984) includes the cyanation of 3-methylpyridine-1-oxide using dimethylcarbamoyl chloride.
None of these references disclose a 3-(2-phenethyl)-1-carbamoyloxypyridinium halide intermediate.